1. An overview of the differences of different JAK inhibitors
Alessandro M. Vannucchi
University of Florence, Italy

2. JAK2 Signaling Abnormalities in MPN

3. JAKs are Involved in Multiple Cytokine Signaling
Vannucchi AM, N Engl J Med. 2010; 363:

4. Dysregulated Cytokine Expression in MF Patients
Verstovsek S et al. NEJM 2010; 363:

5. Abnormally Increased IL-8 and IL2R Plasma Levels Are Prognostically Detrimental
Int-1 (n=27)
All (n=127)
Survival data of (A) all 127 patients and (B) 90 treatment-naive patients with primary myelofibrosis stratified by the presence or absence of interleukin 8 (IL-8) and IL-2R levels that exceed three standard deviations above the normal mean.
Survival data of (A) 27 intermediate-1–risk patients and (B) 70 intermediate-2–risk patients with primary myelofibrosis stratified by the presence or absence of interleukin 8 (IL-8) and IL-2R levels that exceed three standard deviations above the normal mean. Risk categorization is according to the Dynamic International Prognostic Scoring System plus model.5
Int-2 (n=70)
Treatment naive
(n=90)
Tefferi A et al. JCO 2011;29:

6. A portfolio of JAK2 inhibitors
Reddy M et al. Exp Opin Ther targets 2012; 16:313-24

7. A portfolio of JAK2 inhibitors
TYK2
Ruxolitinib
2.7
4.5
322 X
SAR302503
103 3
996
----
CYT387 11 18
155 ?
SB1518
1276 22
1392 Ly
550 VF
2260 wt
Reddy M et al. Exp Opin Ther targets 2012; 16:313-24

8. All JAK2 Inhibitors are Type I and are not Mutation Specific

9. Efficacy of JAK2 Inhibitors: Summary
Spleen response*
Symptoms
Ruxolitinib
42% COMFORT-I
28.5% COMFORT-II Y
Body weight gain
SAR302503
39% overall
45% MTD cohort
66% pts >6cycles
No body weight gain
CYT387
50% overall
*, >35% by MRI (ruxolitinib) or >50% by palpation (SAR & CYT)

10. CYT387: Transfusion Independence Response
Response by Dose (Core Study)
150 mg QD (n=52)
300 mg QD (n=60)
150 mg BID (n=42)
Total1 (n=166)
Transfusion dependent at baseline (evaluable) 24 28 14 68
Transfusion independence rate (12 wks)
63%
75%
57%2
68%
Minimum 2 g/dL increase in hemoglobin level (8 wks)
11% 8%
14%
13%
IWG-MRT anemia response rate
48%
55%
36%
Of the transfusion dependent patients who did not achieve a full transfusion independence response, 23% achieved at least a 50% reduction in transfusion requirement in any 3-month period
Onset and Durability of Response (Core and Extension Study)
Median
Min-Max
Time to confirmed response (12 weeks) (Core; days) 3 85
85-353
Duration of transfusion-free period (12 weeks) (Core and Extension; days) 3
Not yet reached
85-988*
3 additional subjects achieved 12 week transfusion independence response during the Extension Study
1 Includes 100mg QD (n=3), 200mg QD (n=3), and 400mg QD (n=6) doses
2 Not statistically significant vs. 300mg QD
3 Data based on responders
* Ongoing as of November 2012
Pardanani A et al, ASH 2012

11. CYT387: Effects on Anemia
Percentage of Patients Receiving RBC Transfusions in Prior 4 Weeks
Pardanani A et al, ASH 2012

12. Vannucchi AM et al, ASH 2012

13. Effect of TG101348/SAR302503 therapy on JAK2 V617F allele burden
Effect of TG therapy on JAK2 V617F allele burden. Box plot representation of JAK2 V617F allele burden data (A,B) for all mutation-positive patients (n = 51) and (C,D) for the subgroup with baseline allele burden greater than 20% (n = 23). The y-axis represents the JAK2 V617F allele burden from 1.0 (100%) to 0.0 (0%).The change in JAK2 V617F allele burden per cycle of treatment (up to end of cycle 12; ie, C13D1) compared with prestudy baseline is shown (A,C) for the two groups. (B,D) The change at the end of cycle 6 (ie, C7D1) and cycle 12. A significant decrease in JAK2 V617F allele burden compared with prestudy baseline was observed at the end of cycle 6 (B) for the mutation-positive group (P = .04) and (D) for the subgroup with baseline allele burden greater than 20% (P = .002); a similar significant decrease was seen at the end of cycle 12 (B) for the former (P = .01) and (D) latter (P = .002) groups. The Wilcoxon matched-pair signed-rank test was used to compare the median JAK2 V617F allele burden for the comparisons.
Pardanani A et al. JCO 2011;29:

14. Ruxolitinib Induced Inhibition of Inflammatory Cytokines
Verstovsek S et al. NEJM 2010; 363:

15. Inhibition of Inflammatory Cytokines does not Mediate Efficacy of SAR203505
Pardanani A et al, JCO 2011; 29:789-96

16. CYT387: cytokine changes
……….. Our data suggests a cytokine-mediated effect; a majority of patients had treatment-related decrease in circulating IL-1β and IL-1RA levels, which were the only two cytokines associated with transfusion-independence response. Similarly, spleen response was correlated with treatment-associated decreases in a number of cytokines. Overall, these data implicate down-regulation of circulating inflammatory cytokines, further confirmed by gene expression analysis, as the major mechanism for CYT387’s clinical activity in MF.
Pardanani A et al, Leukemia 2013

17. Toxicity of JAK2 Inhibitors: Summary
Courtesy, R. Mesa 2013
Verstovsek S, NEJM 2012; Talpaz M, ASH 2012; Komrojki B, ASH 2012; Pardanani A, Leukemia 2013

18. Conclusions
A portfolio of different JAK2/(1) inhibitors is available in addition to ruxolitinib
There is no clear difference in efficacy against splenomegaly and symptoms
Different JAK2 inhibitors may have different activity against inflammatory cytokines
CYT387 may have unique effects on anemia
Modest activity against JAK2V617F allele burden
Overlapping hematologic toxicity